In an animal model of atherosclerosis, herpesvirus infection causes vascular disease characterized by intimal hyperplasia and foam cell development. Several lines of evidence implicate herpes as potential etiologic agents in the development of human atherosclerosis. Pathophysiological consequences of herpesviral infection of vascular cells include increased production of inflammatory mediators and release of smooth muscle cell (SMC) inflammatory mediators and release of smooth muscle cell (SMC) mitogens, such as platelet-derived growth factor (PDGF). In addition, herpesvirus infection alters the phenotypic expression of vascular smooth muscle cells. The pathway for herpesvirus (HSV) entry into cells remains undefined. Therefore, the identification of those molecular that are responsible for its cellular entry is of paramount importance to develop approaches to alter the course of HSV-induced vascular disease. Our preliminary data suggests that HSV penetrates mesenchymal cells (SMC, EC) via the high-affinity basic fibroblast growth factor (bFGF) receptor. The overall specific aim of this application is to define the cellular and molecular mechanisms involved in HSV penetration into human vascular cells by the bFGF receptor. We will determine the specificity of competitive inhibition by bFGF for HSV binding, uptake, and infectivity of vascular cells; and we will identify those HSV-envelope glycoproteins (such as gB, gD, and gH) which mediate the bFGF receptor occupancy. We will continue our preliminary studies utilizing Chinese Hamster Ovary (CHO) cells transfected with the bFGF receptor gene which overexpress the bFGF receptor in order to define the interaction of HSV glycoproteins with the bFGF receptor. Included in these studies will be computer modeling of the receptor/ligand interaction. Since HSV infection of EC stimulates PDGF release, activation of the bFGF receptor by HSV may mediate HSV-induced PDGF production. Experiments are designed to assess the effect of HSV on 1) PDGF production by EC and SMC 2) PDGF A and B chain mRNA transcript levels; 3) PDGF isoforms. Since bFGF receptor distribution may be a determinant of viral tropism we will determine the distribution and receptor density from various vascular beds at different stages of development. These studies should elucidate the molecular basis for the tropism of this viral pathogen which may participate in early developmental events of the lesion involving intimal SMC proliferation.